Gout is a metabolic disease caused by chronically elevated serum uric acid (sUA) levels (hyperuricemia) due to the disorder of purine metabolism and/or from insufficient renal elimination of uric acid. Deposition of the needle-like crystals of urate in the joints leads to painful inflammatory arthritis. Hyperuricemia, defined as sUA concentration higher or equal to 6.8 mg/dL, may result in the precipitation of urate as mono-sodium salt in the synovial fluid of the human soft tissue, the cartilage of the peripheral joint, the auricle of the ear, and the olecranon bursa of the elbow. When such symptoms are presents, it can be diagnosed as gout. (Terkeltaub R A. Crystal Deposition Diseases. In: Goldman L, Aus-iello D, eds. The Cecil Textbook of Medicine, 23rd ed. Philadelphia, Pa.: Saunders Elsevier Co; 2008:2069-2075; Richette P, Bardin T. Gout. Lancet. 2010, 375(9711):318-328)
Gout is the common type of inflammatory arthritis and has an incidence of approximately 1%-2%. The incidence in the developed countries is relatively high, as a survey of 2007-2008 reported there were about 8.3 million of gout patients in the US. In China, the incidence of gout has dramatically increased in the past decade. It is reported that the number of gout patients in China has exceeded 50 million, and the proportion of men with gout is much higher than that of women.
In the present, gout medications involve short-term treatment for pain relief and reduction of inflammation during an acute attack, the inhibition of uric acid production, and the promotion of uric acid excretion. Medicine for the treatment of acute attack of gout mainly include colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone, and glucocorticoid.
Long-term medications of gout involve decreasing the formation of uric acid and/or increasing uric acid renal excretion. Allopurinol and uloric are the more often used drugs on decreasing the formation of uric acid. The mechanism of these drugs is to reduce the formation of uric acid by inhibiting the xanthine oxidase needed for the transformation of purine to uric acid. Uricosurics are the second class of urate lowering therapy currently available, which act by increasing uric acid renal elimination. They mainly include probenecid, sulphinpyrazone, and benzbromarone etc.
The treatment of acute gout attacks can only control the symptoms and relieve the pain of the patients, but it cannot reduce the concentration of sUA. Colchicine is very toxic, often accompanied by common adverse reactions such as diarrhea, vomiting and abdominal pain spasms. Allopurinol is one of the xanthine oxidase inhibitors. It needs to be used in high dose, and for some people can cause fatal Stevens Johnson syndrome (skin erythema multiforme), often accompanied by stomach discomfort, nausea, diarrhea, headache, fever, loss of appetite, weight loss, pain in urination, hematuria and other side effects. Another xanthine oxidase inhibitor is called uloric (febuxostat), which was launched in Europe and the US in 2009. Although uloric shows good efficacy in lowering uric acid levels in the body, it also has very serious side effects such as cardiovascular problem and gastrointestinal discomfort, potentially causing headaches and liver injury. Benzbromarone has a good uricosuric efficacy, but it leads to fatal liver injury. Both probenecid and sulfinpyrazone are uricosuric agents with high dose administration in poor efficacy and bad side effects.
The mechanism of uricosurics involves the inhibition of the re-absorption of uric acid in the proximal tubular cells to increase the renal excretion of uric acid and reduce the concentration of blood uric acid. About 70% of uric acid excretion in human is by the kidneys, and about 80-85% of hyperuricemia patients is caused by uric acid excretion disorder. (Cheeseman C. Solute carrier family 2, member 9 and uric acid homeostasis. Current Opinion in Nephrology and Hypertension, 2009, 18 (5): 428-432)
Uric acid excretion plays a very important role in the treatment of hyperuricemia and gout. Human urate anion transporter 1 (hURAT1) is located in the proximal tubular epithelial cell membrane, and it belongs a super family member of an organic anion transporter (OAT), which is encoded by SLC22A12 gene. Its cDNA has several mutations that cause uric acid metabolism abnormally. A Meta analysis showed that this gene has 0.13% variables contributed to serum uric acid level. (So A, Thorens B. Uric acid transport and disease. Journal of Clinical Investigation., 2010, 120 (6): 1791-1799)
The URAT1 controls more than 90% of the uric acid re-absorption after glomerular filtration. Therefore, selective inhibition of URAT1 can decrease the re-absorption of uric acid and promote the excretion of uric acid in the kidneys to reduce uric acid levels in the body. (Michael F W, Jutabha P, Quada B. Developing potent human uric acid transporter 1 (hURAT1) inhibitors. Journal of Medicinal Chemistry. 2011, 54:2701-2713)
Currently, benzbromarone as the URAT1 inhibitor is still widely used in the market for the treatment of gout. Its chemical name is (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-benzofuran-3-yl)methanone, which was developed by France Snaofi-Synthelabo company and launched in 1976. It is the most effective uricosuric agent in the market and has been used for nearly 40 years. But the use of benzbromarone has not been approved in the US and was withdrawn from most European markets in 2003 due to its side effect of severe liver toxicity. (Jansen T L, Reinders M K, van Roon E N, et al. Benzbromarone withdrawn from the European market: another case of “absence of evidence is evidence of absence”. Clinical Experimental Rheumatology, 2004, 22(5): 651) Another disadvantage is that it has a strong inhibitory effect on the liver CYP2C9 enzyme. However, more than 20 countries, such as China, Germany, Japan, Brazil, and New Zealand still widely use it because of the lack of good gout drugs on the market.

Studies have shown that the fulminant or fatal liver injury of benzbromarone has been associated with its reactive metabolites. A possible mechanism of liver toxicity may involve the bioactivation of benzbromarone through sequential hydroxylation of the benzofuran ring to form 6-hydroxy-benzbromarone and a catechol by CYP2C9, which can be further oxidized by P450s enzymes to a reactive quinone metabolite capable of adducting thiol reagents/cysteine residues. (Matthew G. McDonald, Rettie A E. Sequential metabolism and bioactivation of the hepatotoxin benzbromarone: formation of glutathione adducts from a catechol intermediate. Chemical Research in Toxicology. 2007, 20 (12):1833-1842)
Benzbromarone also has other side effects, such as diarrhea, stomach discomfort, nausea, digestive system symptoms, skin allergies such as macula, flush, itching, and so on.
Currently, severe side effects from either the uricosuric agents or xanthine oxidase inhibitors have greatly affected the long-term use of these gout medicines. Therefore, it is critical to develop gout drugs that are highly effective and have low toxicity.